2-amino-1-(5-amino-1h-imidazol-4-yl)ethanone and method of preparation

ABSTRACT

2-Amino-1-(5-amino-1H-imidazol-4-yl)ethanone, 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one and acid-addition salts thereof are disclosed. 2-Amino-1-(5-amino-1H-imidazol-4-yl)ethanone and its acid-addition salts are prepared by catalytically reducing an acid-addition salt of 2-amino-1-[5-amino-1-(protected)-1H-imidazol-4-yl]ethanone. 6,7-Dihydroimidazo[4,5-d][1,3]-diazepin-8(3H)-one and its acid-addition salts are prepared by reacting an acid-addition salt of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone with a compound able to contribute a formyl group. The later product may subsequently be converted into (R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol. Furanose derivatives of 6,7-dihydroimidazo[4,5-d][1,3]diazepine are also disclosed and their methods of preparation. Lastly, a method for resolving an isomer mixture of 3-(2-deoxy-β-D-erythro-pentafuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol compounds is related.

SUMMARY AND DETAILED DESCRIPTION

The present invention relates to new imidazoles. More particularly, theinvention relates to new imidazoles of the formulae ##STR1## andacid-addition salts thereof. The preferred compounds are the newimidazoles in the form of their acid-addition salts since the free basesare of a low order of stability under ordinary circumstances.

The invention also relates to furanose derivatives of6,7-dihydroimidazo[4,5-d][1,3]diazepines having the formula ##STR2## andacid-addition salts thereof wherein Z is ˜OH or ═O and R is hydrogen orAcyl.

In addition, the invention relates to methods for producing these newimidazole compounds and a method employing these new imidazole compoundsin preparing(R)-3-(2-deoxy-β-D-erythropentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol(pentostatin).

In accordance with the invention, acid-addition salts of6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one can be produced byreacting a di-acid-addition salt of2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone with a compound capable ofdonating a formyl group, such as (lower alkyl-O)₃ CH, (acyl-O)(HN═)CH.HX, (lower alkyl-O)(HN═)CH.HX, (NH₂)(HN═)CH.HX, etc. wherein Xis an anion.

The preferred formylating reagents are methyl or ethyl orthoformate andX being chloride.

The reaction is generally carried out in a lower alkyl alcohol,preferably ethanol, although other solvents may also be used such asdimethylsulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide ormixtures of the above named solvents. While time and temperature may bevaried, a range of about 50° C. to about 150° C. for about 30 minutes toabout 6 hours is generally employed, preferably 75° C. to 85° C. for 1to 2 hours. While the ratio of reactants is not critical, an excess ofthe formylating agent is generally preferred. The product is isolated inthe form of its acid-addition salt, but may be converted to itsrelatively unstable free base by the addition of base, such asmethanolic sodium hydroxide.

The term "lower alkyl" is intended to mean an alkyl group of from one tosix carbon atoms, such as methyl, ethyl, butyl and isopentyl.

The term "acid-addition salt" is intended to mean a salt such as thehydrochloride, sulfate, acetate, benzoate, citrate, hydrobromide,nitrate, etc.

The term "Acyl" is intended to mean ##STR3## wherein R is a relativelyinert organic radical, preferably an organic radical having up to 12carbon atoms.

Also in accordance with the invention, di-acid-addition salts of2-amino-(5-amino-1H-imidazol-4-yl)ethanone may be prepared bycatalytically reducing a di-acid-addition salt, preferably thedihydrochloride, of2-amino-1-[5-amino-1-(arylmethyl)-1H-imidazol-4-yl]ethanone. The term"aryl" is intended to mean any aromatic group that facilitates thereductive cleavage of the adjacent CH₂ -- N bond, preferably phenyl. Thecatalysts are generally noble metals such as Pd, Pt or Rh or oxidesthereof. In addition, the catalyst may be supported on a carrier such ascarbon with the preferred catalyst system being Pd-on-carbon. Hydrogenmay be bubbled into the reaction medium or the reaction may be carriedout in a hydrogen atmosphere at pressures of up to about fouratmospheres. Generally polar solvents are employed such as water, loweralkyl alcohols, lower alkyl carboxylic acids or mixtures of theforegoing. A preferred solvent system uses water-methanol-acetic acid.While time and temperature are not critical, the reaction is generallyconducted at a temperature range of about 15° C. to 35° C. untilhydrogen absorption ceases. The product is isolated in the form of anacid-addition salt (usually two moles of acid per mole of imidazolecompound). While the acid-addition salts, especially the di-acid salts,are preferred, the unstable free base may be prepared by the addition ofa base.

The 2-amino-1-[5-amino-1-(arylmethyl)-1H-imidazol-4-yl]ethanonedihydrochloride is prepared by reducing a2-nitro-1-[5-nitro-1-(arylmethyl)-1H-imidazol-4-yl]ethanone usingstannous chloride dihydrate in concentrated hydrochloric acid.

The 2-nitro-1-[5-nitro-1-(arylmethyl)-1H-imidazol-4-yl]ethanones areprepared by first coupling a5-nitro-1-(arylmethyl)-1H-imidazole-4-carboxylic acid to1,1'-carbonyldiimidazole and reacting this product with the anion ofnitromethane.

The 5-nitro-1-(arylmethyl)-1H-imidazole-4-carboxylic acids are preparedby treating (E)-5-nitro-4-(2-phenylethenyl)-1-(arylmethyl)-1H-imidazolesinitially with ozone followed by performic acid.

The (E)-5-nitro-4-(2-phenylethenyl)-1-(arylmethyl)-1H-imidazoles areprepared by treating (E)-5-nitro-4-(2-phenylethenyl)-1H-imidazole [Ber.56, 683 (1923)] with an arylmethyl bromide or iodide in the presence ofanhydrous potassium carbonate.

This invention also relates to a method for converting the compounds ofthis invention into the potent deaminase inhibitor(R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-D][1,3]diazepin-8-ol(pentostatin), which is the subject matter of U.S. Pat. No. 3,923,785,which is incorporated by reference. This deaminase inhibitor potentiatesthe activity of the known antiviral agent,9-(β-D-arabinofuranosyl)adenine.

Thus in accordance with the invention,(R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-D][1,3]diazepin-8-ol,having the structure ##STR4## is separated from mixtures of two isomershaving the following formula ##STR5## using a reverse-phasechromatographic procedure. A derivatized column of silica gel, whereinsaid derivative is a lipophilic moiety, perferably the octadecylsilylderivative, is eluted with a polar solvent such as water, methanol,ethanol or mixtures thereof, preferably 95:5 water-methanol.

The isomer mixture may be obtained by reducing a compound of theinvention having the formula ##STR6## which has the name3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-one,or an acid-addition salt thereof. The reduction may preferably beachieved by using a borohydride, such as sodium borohydride, potassiumborohydride, lithium borohydride, tetra(lower-alkyl)ammoniumborohydride.

In addition, the reduction may be carried out employing diborane and itsderivatives such as thexylborane, 9-borobicyclononane, etc., alkalimetal derivatives of triloweralkyl boranes, such as lithium or potassiumtri-sec-butylborane, or aluminum hydrides, such as lithium aluminumhydride, allane, di-lower alkylallane, sodiumbis(2-methoxyethoxy)aluminum hydride.

The use of the above reagents in effecting the reduction is taught inthe references: H.O. House, "Modern Synthetic Reactions," 2nd Edition,Benjamin (Menlo Park, Calif.), 1972, pp. 45-130 and C. A. Buehler and D.E. Pearson, "Survey of Organic Syntheses," Wiley-Interscience (NewYork), 1970, pp. 193-212, which are incorporated by reference.

In addition, the ketone may be reduced using a catalyst in the presenceof molecular hydrogen. Choice catalysts would be ruthenium, platinum,platinum oxide, palladium, copper chromite, certain transition-metalcomplexes, etc. The catalysts may be on standard supports, such ascarbon.

The use of catalytic processes is reported in the following references:R. L. Augustine, "Catalytic Hydrogenation," Marcel Dekker (New York),1965, pp. 81-88 and C. A. Buehler and D. E. Pearson, "Survey of OrganicSyntheses," Wiley-Interscience (New York), 1970, p. 201, which areincorporated by reference.

The compound of the formula ##STR7## is prepared by deprotecting acompound of the formula ##STR8## using a strong base, preferably analkali metal lower alkoxide such as sodium methoxide in a polar solvent,preferably an alcohol such as methanol. The reaction is carried out in atime period of from a few minutes to about 3 hours at from about 0° C.to about 70° C.

In addition, the mixture of two isomers having the following formula##STR9## may be obtained by deprotecting a compound of the inventionhaving the formula ##STR10## which has the name6,7-dihydro-3-[3,5-di-O-(p-toluoyl)-α,β-D-erythro-pentofuranosyl]-imidazo[4,5-d][1,3]-diazepin-8(3H)ol,or an acid-addition salt thereof wherein acyl is as previously definedand is preferably p-methylbenzoyl. The deprotection is carried outemploying a strong base in a polar solvent at temperatures from about 0°C. to about 50° C., preferably 25° C., for periods of from about a fewminutes to about 12 hours, preferably 1 hour.

The preferred base is an alkali metal lower alkoxide, such as sodiummethoxide, in an alcohol, such as methanol.

The foregoing di-acyl protected compound is prepared by reducing acompound having the formula ##STR11## wherein Acyl is as previouslydefined and is preferably p-methylbenzoyl. The same reduction proceduresgiven earlier for the reduction of compounds of the formula ##STR12##are employed.

The preferred process utilizes sodium borohydride in a polar solventsuch as water, lower alkyl alcohols or mixtures thereof. Temperatures offrom 0° C. to 50° C. for periods of from a few minutes to about 3 hoursare generally employed.

The compound of the formula ##STR13## wherein Acyl is as previouslydefined and preferably p-methylbenzoyl is prepared by coupling acompound of the formula ##STR14## in the presence ofbis(trimethylsilyl)acetamide, with a compound of the formula ##STR15##

The invention is illustrated by the following examples.

EXAMPLE 1 2-Amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride

A solution of 1.0 g. of2-amino-1-[5-amino-1-(phenylmethyl)-1H-imidazol-4-yl]ethanonedihydrochloride in 100 ml. of 70:20:10 methanol:water:acetic acid ishydrogenated over 0.52 g. of 20% palladium-on-carbon at 50 p.s.i. untilhydrogen uptake ceases. The catalyst is removed by filtration and thefiltrate is evaporated at reduced pressure to give2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride; m.p. above250° dec.

INTERMEDIATES a. Mixture of(E)-5-nitro-4-(2-phenylethenyl)-1-(phenylmethyl)-1H-imidazole and(E)-4-nitro-5-(2-phenylethenyl)-1-(phenylmethyl)-1H-imidazole

A well-stirred suspension of 215.2 g. of(E)-5-nitro-4-(2-phenylethenyl)-1H-imidazole [Ber., 56, 683 (1923)] in1.6 l. of dry dimethylformamide, protected from moisture, is treated inturn with 207.3 g. of anhydrous potassium carbonate, then with 205 g. ofbenzyl bromide over a 15 minute period. The mixture is stirred andheated at 75° C. for 2 hours, then cooled to about 15° C. and filtered.The filter cake of inorganic salts is washed well with dichloromethane.The filtrate and washings are combined and evaporated at reducedpressure. The residual oil is evaporated several times with xylene underreduced pressure to remove traces of dimethylformamide. The residue ispartitioned between 500 ml. of water and 2 l. of dichloromethane. Theorganic phase is separated, dried and evaporated. The residual partiallycrystalline mass is dissolved in a minimum amount of boiling chloroform.The hot chloroform solution is diluted with 7 l. of boiling cyclohexane,then treated with a small amount of chloroform to clarify thecloudiness. The resulting solution is cooled slowly, with vigorousstirring, to 5° C. The crystalline precipitate consisting of a 3:1mixture of (E)-5-nitro-4-(2-phenylethenyl)-1-(phenylmethyl)-1H-imidazoleand (E)-4-nitro-5-(2-phenylethenyl)-1-(phenylmethyl)-1H-imidazole iscollected by filtration, washed with cyclohexane and dried; m.p. 90°-92°C.

b. 5-Nitro-1-(phenylmethyl)-1H-imidazole-4-carboxylic acid

A stream of 6% ozone in dry oxygen is bubbled at a rate of 1.7 l./minuteinto a solution of 138.6 g. of a 3:1 mixture of(E)-5-nitro-4-(2-phenylethenyl)-1-(phenylmethyl)-1H-imidazole and(E)-4-nitro-5-(2-phenylethenyl)-1-(phenylmethyl)-1H-imidazole in 2.3 l.of dichloromethane at -78° C. for 5 hours, while protecting the systemfrom moisture. An excess of ozone is present as evidenced by its bluecolor. The solution is allowed to warm to -30° C., while removing theexcess ozone by a dry nitrogen purge. The solution is then evaporated atreduced pressure and the residual oil dissolved promptly in 433 ml. of97% formic acid. The formic acid solution is treated dropwise, withstirring and cooling to 0°-5° C., with 173 ml. of 30% hydrogen peroxide.The mixture is stirred at room temperature for 16 hours and theresulting precipitate is collected by filtration and washed with water.The solid is suspended in 5 l. of water and the pH is adjusted to 10-11with concentrated aqueous ammonia. After stirring 1 hour, the solutionis filtered to remove insolubles. The pH of the filtrate is adjusted to2 with concentrated hydrochloric acid. The resulting precipitate of5-nitro-1-(phenylmethyl)-1H-imidazole-4-carboxylic acid is collected byfiltration, washed well with water and dried; m.p. 151°-152° C.

c. 2-Nitro-1-[5-nitro-1-(phenylmethyl)- 1H-imidazol-4-yl]ethanone

A mixture of 67.8 g. of5-nitro-1-(phenylmethyl)-1H-imidazole-4-carboxylic acid and 72.9 g. of1,1'-carbonyldiimidazole in 800 ml. of dry tetrahydrofuran, protectedfrom moisture, is heated at reflux for 1 hour. The resulting solution isevaporated at reduced pressure and the residual oil is dissolved in 450ml. of dichloromethane. The solution is washed quickly with 100 ml. ofice water, dried promptly and evaporated at reduced pressure to give theimidazolide. A solution of this imidazolide in 800 ml. oftetrahydrofuran is added dropwise, with vigorous stirring, to a solutionof 36.9 g. of potassium tert-butoxide and 65 ml. of nitromethane in 600ml. of tetrahydrofuran, with the exclusion of moisture. The mixture isstirred at room temperature for 16 hours and the resulting solidcollected by filtration and washed thoroughly with dichloromethane. Thesolid is suspended in 600 ml. of water and the pH adjusted to 3 withconcentrated hydrochloric acid. The suspension is repeatedly extractedwith 200 ml. portions of ethyl acetate, with the pH being readjusted to3 before each extraction. The combined extract is dried, decolorizedwith activated charcoal and evaporated at reduced pressure to give2-nitro-1-[5-nitro-1-(phenylmethyl)-1H-imidazol-4-yl]ethanone; m.p.105°-107° C.

d. 2-Amino- 1-[5-amino-1-(phenylmethyl)-1H-imidazol-4-yl]-ethanonedihydrochloride

A stirred solution of 38 g. of stannous chloride dihydrate in 100 ml. ofconcentrated hydrochloric acid is treated portionwise with 10 g. of2-nitro-1-[5-nitro-1-(phenylmethyl)-1H-imidazol-4-yl]ethanone. Ten ml.of ethanol are added to clarify the solution and the mixture is stirredat 60° C. for 3 hours. The solution is evaporated to near dryness andthree 100 ml. portions of ethanol are added sequentially and evaporatedfrom the residue. The residual syrup is stirred with 800 ml. of etherand the resulting solid is collected by filtration, washed with etherand dried at reduced pressure. This solid (a tin complex) is dissolvedin 150 ml. of water and the tin is precipitated as the sulfide bybubbling hydrogen sulfide gas into the solution. The mixture is filteredand the filter cake washed with water. The filtrate and washings arecombined and evaporated at reduced pressure. The residue is repeatedlyevaporated with 100 ml. portions of ethanol. The final residual gum istriturated with 30 ml. of ethanol to give as a crystalline solid2-amino-1-[5-amino-1-(phenylmethyl)-1H-imidazol-4-yl]ethanonedihydrochloride, which is collected by filtration, washed with ethanoland dried at reduced pressure; m.p. 155° C. (dec.).

EXAMPLE 2 6,7-Dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-onemonohydrochloride

A mixture of 285 mg. of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanonedihydrochloride (Example 1), 200 ml. of absolute ethanol and 10 ml. oftriethyl orthoformate is stirred and heated at reflux for 1 hour, thencooled and evaporated at reduced pressure. The residue of6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one monohydrochloride,which crystallizes on standing, is collected by filtration, washed withethanol, then with ether, and dried at reduced pressure; m.p. above 250°C. dec.

EXAMPLE 36,7-Dihydro-3-[3,5-di-O-(p-toluoyl)-α,β-D-erythro-pentofuranosyl]-imidazo[4,5-d][1,3]diazepin-8(3H)-one

A suspension of 450 mg. of6,7-dihydroimidazo[4,5-d]-[1,3]diazepin-8(3H)-one monohydrochloride(Example 2) in 5 ml. of acetonitrile is treated with 2 ml. ofbis(trimethylsilyl)acetamide, stirred at room temperature for 16 hours,then evaporated at reduced pressure. The residue is dissolved in 5 ml.of dry 1,2-dichloroethane and the solution is treated with 1.0 g. of3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride [Ber., 93, 2777(1960)]. The resulting solution is evaporated at reduced pressure. Theresidue is then heated at 80°-110° C. under reduced pressure for 1 hour.The residue is dissolved in a mixture of 25 ml. of ethyl acetate and 25ml. of saturated aqueous sodium bicarbonate and the two-phase system isclarified by filtration. The filtration is evaporated at reducedpressure and the residue is applied to the top of a 1.9 × 60 cm. columnof silica gel. The column is eluted with a gradient of 500 ml. of ethylacetate to 500 ml. of 9:1 ethyl acetate/methanol, while collecting 4-ml.fractions. Those fractions (nos. 45-58) containing the desired product(as determined by TLC) are combined and evaporated at reduced pressureto give6,7-dihydro-3-[3,5-di-O(p-toluoyl-α,β-D-erythro-pentofuranosyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one.

EXAMPLE 4 Mixture containing(R)-3-(2-deoxy-α-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol(pentostatin)

A solution of 25 mg. of 6,7-dihydro-3-[3,5-di-O-(p-toluoyl)-60,β-D-erythro-pentofuranosyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one in 5ml. of ethanol is treated with 10 mg. of sodium borohydride and stirredat room temperature for 15 minutes. About 5 mg. of sodium is then added,the solution is stirred at room temperature for 15 minutes, thenneutralized with carbon dioxide. The mixture is evaporated at reducedpressure and the residue is partitioned between 10 ml. of ether and 10ml. of water. The aqueous phase is separated and evaporated at reducedpressure. The residue is applied to the top of a 1 × 10 cm. column ofDowex 50×2 resin (a strongly acidic cation exchange resin) in theammonium form. The resin is eluted with 25 ml. of 0.01N aqueous ammoniaand the eluate is evaporated at reduced pressure to give a residueconsisting of a mixture of the four possible isomers, one of which is(R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol(pentostatin).

EXAMPLE 56,7-Dihydro-3-[3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-imidazo[4,5-d][1,3]diazepin-8(3H)-one

Bis(trimethylsilyl)acetamide, 68 ml., is added to 11.20 g. of6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one hydrochloride suspendedin 112 ml. of acetonitrile and the mixture is stirred, under dryconditions for 0.5 hours, at the end of which time the excess reagent isremoved at 40° C./0.1 mm. A solution of 24.23 g. of3,5-di-o-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride in 30 ml. ofdry 1,2-dichloroethane is added to the syrupy (trimethyl)silylatedheterocycle, and the solvent is evaporated. The resulting gum is fusedat 100°/10 mm. for 24 minutes, at the end of which time the reactionmixture is triurated in 300 ml. of aqueous sodium bicarbonate solutionfor about 0.5 hours, then extracted with 200 ml. of ethyl acetate. Themagnesium sulfate dried extract is passed across a column of 250 g. ofsilica gel and eluted sequentially with 1 liter each of ethyl acetate,5%, 10% and 15% methanolic ethyl acetate. The desired products eluteswith the 10% methanolic solvent. The solvent is removed by evaporationin vacuo, and the α product is crystallized from 150 ml. of hot ethylacetate (m.p. 220° dec).

The mother liquors were evaporated, and from warm ethyl acetate wasdeposited crystals of the above named β-anomer (m.p. 129° C., softensand melts at 155° C.).

EXAMPLE 66,7-Dihydro-3-(β-D-erythro-pentofuranosyl)imidazo[4,5-d][1,3]diazepin-8(3H)-one

Metallic sodium (25 mg.) is added to a suspension of 1.52 g. of the6,7-dihydro-3-[3,5-di-O-(p-toluoyl)-β-D-erythropentofuranosyl]imidazo[4,5-d][1,3]diazepin-8(3H)-onein 30 ml. of dry methanol. The mixture soon goes into solution, andanalysis by tlc (silica gel, 9:1 chloroform-methanol) indicated completereaction to give the free nucleoside within 45 minutes at 23°-25°. Solidcarbon dioxide is added to neutralize the base, and the mixture isvaporated to dryness. The residue is extracted with ether and dried invacuo to give a mixture of the nucleoside and sodium carbonate; λ^(MeOH)_(max) = 232 (E'_(') 442), 298 (57) and 346 nm. (92); the E'_(') showsca. 50% nucleoside in the salt-nucleoside mixture.

EXAMPLE 73-(2-Deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8ol

The crude nucleoside obtained in Example 6 is dissolved in 50 ml. ofwater and 60 mg. of sodium borohydride is added, portionwise, withstirring. After 40 minutes, the excess reducing agent is decomposed bythe addition of solid carbon dioxide, and the solution is lyophilized todryness. The salts are removed by chromatography over SP-Sephadex [NH₄ ⁺] [a sulfonylpropyl-derivatized dextran polymer; alternatively asulfonic acid resin such as Dowex-50 [NH₄ ⁺ ] can be used]; elution waswith water, then with 0.01N ammonium hydroxide, which caused immediateelution of R-- and S-- forms of the above compound.

EXAMPLE 8(R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol

The mixture of R and S-nucleoside isomers obtained in Example 7 isloaded onto a 0.9×60 cm. column of a reverse-phaseoctadecylsilyl-derivatized column of silica gel and eluted with 95:5water-methanol. After 20 minutes of elution (5.5 ml./minute, 2000 psi)the S-isomer appears, followed by the R-isomer at 25.5 minutes. Theproducts are isolated as lyophilized powders. R-isomer:

[α]_(D) ²³ = +76°, [α]₃₆₅ ²³ = +630° (c 1, water)

We claim:
 1. A compound having the name2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone and acid-addition saltsthereof.
 2. The compound of claim 1 wherein said acid-addition salt isthe dihydrochloride.
 3. A process for the preparation of a compound ofclaim 1 which comprises reducing2-amino-1-[5-amino-1-(arylmethyl)-1H-imidazol-4-yl]ethanone or anacid-addition salt thereof.